2-(2,6-Dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester | 124317-40-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(2,6-Dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester
• 英文别名: Ethyl 2-(2,6-dimethylphenoxy)-2-methylpropanoate
• CAS: 124317-40-4
• 化学式: C₁₄H₂₀O₃
• 分子量: 236.311
• InChiKey: MOYYIVORVYLLSK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(2,6-Dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester 在 三乙基硅烷 、 aluminum (III) chloride 、 caesium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 25.0h， 生成 ethyl 2-(4-(2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropanoate
  参考文献：
  名称：

  发现第一个用于治疗胆汁淤积性肝病的亚纳摩尔 PPARα/δ 双激动剂

  摘要：

  过氧化物酶体增殖物激活剂受体 α/δ (PPARα/δ) 被认为是通过改善肝脏胆汁淤积、炎症和纤维化来治疗胆汁淤积性肝病 (CLD) 的潜在药物靶点。在这项工作中，我们开发了一系列乙内酰脲衍生物作为有效的 PPARα/δ 双重激动剂。代表性化合物V1表现出亚纳摩尔水平的 PPARα/δ 双重激动活性（PPARα EC 50 = 0.7 nM；PPARδ EC 50 = 0.4 nM），并且比其他相关核受体表现出优异的选择性。晶体结构以 2.1 Å 分辨率揭示了V1和 PPARδ 的结合模式。重要的是，V1表现出优异的药代动力学 (PK) 特性和良好的安全性。值得注意的是，V1在极低剂量（0.03 和 0.1 mg/kg）的临床前模型中显示出有效的抗慢性肺病和抗纤维化作用。总的来说，这项工作为治疗慢性肺病和其他肝纤维化疾病提供了一种有前途的候选药物。

  DOI：

  10.1021/acs.jmedchem.2c02123
• 作为产物：
  描述：

  2-溴-2-甲基丙酸乙酯 、 2,6-二甲基苯酚 在 caesium carbonate 作用下， 以 乙腈 为溶剂， 以51%的产率得到2-(2,6-Dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester
  参考文献：
  名称：

  作为治疗非酒精性脂肪性肝炎的有效 PPARα/δ 双重激动剂的三唑酮衍生物的设计、合成和生物学评价

  摘要：

  过氧化物酶体增殖物激活受体α/δ（PPARα/δ）被认为是非酒精性脂肪性肝炎（NASH）的潜在治疗靶点。然而，PPARα/δ双重激动剂GFT-505在III期临床试验中表现出较差的抗NASH效果，这可能是由于其PPARα/δ激动活性较弱且代谢稳定性差。其他报道的 PPARα/δ 双重激动剂要么表现出有限的效力，要么具有不平衡的 PPARα/δ 激动活性。在此，我们报道了一系列新型三唑酮衍生物作为 PPARα/δ 双重激动剂。其中，化合物H11在 PPAR 反式激活测定中表现出有效且平衡的 PPARα/δ 激动活性（PPARα EC 50 = 7.0 nM；PPARδ EC 50 = 8.4 nM）以及对 PPARγ 的高选择性（PPARγ EC 50 = 1316.1 nM）。 PPARδ 与H11复合物的晶体结构揭示了独特的 PPARδ-激动剂相互作用。 H11具有优异的 PK 特性和良

  DOI：

  10.1021/acs.jmedchem.1c02002

文献信息

• [EN] HYDANTOIN COMPOUND AND MEDICAL USE THEREOF<br/>[FR] COMPOSÉ HYDANTOÏNE ET SON UTILISATION MÉDICALE<br/>[ZH] 海因类化合物及其医药用途
  申请人：HARBIN MEDISAN PHARMACEUTICAL CO LTD

  公开号：WO2023138302A1

  公开（公告）日：2023-07-27

  提供了式（I）所示的海因类化合物或其药学上可接受的盐及其医药用途。该类化合物对PPARα和PPARδ具有强效激动作用，对PPARγ具有较好选择性，且具有良好的药物代谢动力学性质。该类化合物或其药学上可接受的盐、前药、氘代化合物或溶剂化物可应用于制备PPARα/δ双重激动剂，用于制备预防或治疗PPARα和/或PPARδ介导的疾病的药物。
• Potential antisecretory antidiarrheals. 2. .alpha.2-Adrenergic 2-[(aryloxy)alkyl]imidazolines
  作者：Alan E. Moormann、Barnett S. Pitzele、P. H. Jones、Gary W. Gullikson、David Albin、Stella S. Yu、Robert G. Bianchi、Elizabeth L. Sanguinetti、Barbara Rubin

  DOI：10.1021/jm00164a024

  日期：1990.2

  Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.